Cancer Chemotherapy and Pharmacology

, Volume 70, Issue 4, pp 503–511 | Cite as

A phase 1 study of vinflunine in combination with trastuzumab for the treatment for HER2-positive metastatic breast cancer

  • R. Paridaens
  • O. Rixe
  • M. C. Pinel
  • H. Wildiers
  • G. Zorza
  • P. FerréEmail author
  • H. Roche
Original Article



To determine the recommended dose (RD) of vinflunine in combination with trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and to investigate potential pharmacokinetic (PK) interactions.

Patients and methods

In the first part of the study, two dose levels of vinflunine given every 3 weeks were explored (280 and 320 mg/m2) combined with trastuzumab (4 mg/kg loading dose and 2 mg/kg weekly). For each level of dose, six patients were enrolled to determine the RD for phase 2 studies (RP2S). In the second part of the study, 18 additional patients at RP2S have been evaluated to confirm safety and investigate preliminary antitumor activity.


The RD was 320 mg/m2 according to the dose escalation plan. Eleven of 15 additional patients who received this dose experienced dose-limiting toxicities, leading to a reduction in the RD to 280 mg/m2. When compared to prior trials when vinflunine was used as a single agent, neither vinflunine total blood clearance nor trastuzumab serum concentrations were modified when the drugs were combined. All patients were evaluable, and the overall response rate was 73.3 % (95 % CI 54.1–87.7). The median progression-free survival was 11.3 months (95 % CI 9.4–21.0). At the dose of 280 mg/m2, grade 3–4 neutropenia were seen in 4 patients (44.4 %) without febrile neutropenia. Non-hematologic grade 4 toxicities were not reported while grade 3 peripheral sensory neuropathy concerned 2 patients (22.2 %).


The RD of vinflunine in combination with the standard regimen of trastuzumab is 280 mg/m2 every 3 weeks. No mutual PK drug–drug interaction was seen. This regimen appears to be active with a favorable safety profile. Its role in HER2-positive MBC treatment needs to be defined in prospective comparative clinical trials.


HER2 Metastatic breast cancer Phase I Trastuzumab Vinflunine Pharmacokinetics 


  1. 1.
    American Cancer Society (2005) Cancer facts and figures. American Cancer Society, Atlanta Google Scholar
  2. 2.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182PubMedCrossRefGoogle Scholar
  3. 3.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRefGoogle Scholar
  4. 4.
    Demonty G, Bernard-Marty C, Puglisi F, Mancini I, Piccart M (2007) Progress and new standards of care in the management of HER-2 positive breast cancer. Eur J Cancer 43:497–509PubMedCrossRefGoogle Scholar
  5. 5.
    Beslija S, Bonneterre J, Burstein HJ, Cocquyt V, Gnant M, Heinemann V, Jassem J, Kostler WJ, Krainer M, Menard S, Petit T, Petruzelka L, Possinger K, Schmid P, Stadtmauer E, Stockler M, Van Belle S, Vogel C, Wilcken N, Wiltschke C, Zielinski CC, Zwierzina H (2009) Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 20:1771–1785PubMedCrossRefGoogle Scholar
  6. 6.
    Pegram MD, Konecny GE, O’Callaghan C, Beryt M, Pietras R, Slamon DJ (2004) Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 19(96):739–749CrossRefGoogle Scholar
  7. 7.
    Aapro M, Finek J (2012) Oral vinorelbine in metastatic breast cancer: a review of current clinical trial results. Cancer Treat Rev 38:120–126PubMedCrossRefGoogle Scholar
  8. 8.
    Fahy J, Duflos A, Ribet JP, Jacquesy JC, Berrier C, Jouannetaud M, Zunino F (1997) Vinca alkaloids in superacidic media: a method for creating a new family of antitumor derivatives. J Am Chem Soc 119:8576–8577CrossRefGoogle Scholar
  9. 9.
    Zorza G, Pellerin D, Fortune V, Puozzo C (2010) A simple and sensitive high-performance liquid chromatographic method for the determination of vinflunine and 4-O-deacetylvinflunine from human blood. Ther Drug Monit 32:734–740PubMedCrossRefGoogle Scholar
  10. 10.
    Nguyen L, Retout S, and Mentre Fea (2002) Population pharmacokinetics of vinflunine from phase I data and evaluation of population sampling designs for further clinical development. In: Proceedings of annual meeting of the population approach group in Europe, 11Google Scholar
  11. 11.
    Maple L, Lathrop R, Bozixh S, Harman W, Tacey R, Kelley M, Danilkovitch-Miagkova A (2004) Development and validation of ELISA for Herceptin detection in human serum. J Immunol Methods 295:169–182PubMedCrossRefGoogle Scholar
  12. 12.
    Vermorken JB, Stupp R, Nguyen L (2003) Phase I study of IV vinflunine given on a weekly schedule in previously untreated patients with advanced solid tumours. Proc Am Soc Clin Oncol 22:221 (Abstract 887)Google Scholar
  13. 13.
    Bennouna J, Fumoleau P, Armand JP, Raymond E, Campone M, Delgado FM, Puozzo C, Marty M (2003) Phase I and pharmacokinetic study of the new vinca alkaloid vinflunine administered as a 10-min infusion every 3 weeks in patients with advanced solid tumours. Ann Oncol 14:630–637PubMedCrossRefGoogle Scholar
  14. 14.
    Johnson P, Geldart T, Fumoleau P, Pinel MC, Nguyen L, Judson I (2006) Phase I study of vinflunine administered as a 10-minute infusion on days 1 and 8 every 3 weeks. Invest New Drugs 24:223–231PubMedCrossRefGoogle Scholar
  15. 15.
    CPMP Committee for Proprietary Medicinal Products. Note for guidance on the investigation of drug interactions EMEA—CPMP/ENP/560/95. 17 Dec 1997Google Scholar
  16. 16.
    Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639–2648PubMedGoogle Scholar
  17. 17.
    Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, Karlsson P, Tange UB, Sorensen PG, Moller S, Bergh J, Langkjer ST (2011) Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol 20(29):264–271CrossRefGoogle Scholar
  18. 18.
    Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, Von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ (2011) Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol 29:149–156PubMedCrossRefGoogle Scholar
  19. 19.
    Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D (2006) Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 20(24):2786–2792CrossRefGoogle Scholar
  20. 20.
    Gennentech, Inc. (2010) Full prescribing information on trastuzumab, final labelling, 1029Google Scholar
  21. 21.
    Campone M, Cortes-Funes H, Vorobiof D, Martin M, Slabber CF, Ciruelos E, Bourbouloux E, Mendiola C, Delgado FM, Colin C, Aslanis V, Fumoleau P (2006) Vinflunine: a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy. Br J Cancer 95:1161–1166PubMedCrossRefGoogle Scholar
  22. 22.
    Fumoleau P, Cortes-Funes H, Taleb AB, Chan S, Campone M, Pouget JC, Tubiana-Hulin M, Slabber CF, Caroff-Paraiso I, Alberts AS, Ben Ayed F (2009) Phase 2 study of single-agent IV vinflunine as third-line treatment of metastatic breast cancer after failure of anthracycline-/taxane-based chemotherapy. Am J Clin Oncol 32:375–380PubMedCrossRefGoogle Scholar
  23. 23.
    Zhou H, Mascelli MA (2011) Mechanisms of monoclonal antibody–drug interactions. Annu Rev Pharmacol Toxicol 51:359–372PubMedCrossRefGoogle Scholar
  24. 24.
    Seitz K, Zhou H (2007) Pharmacokinetic drug–drug interaction potentials for therapeutic monoclonal antibodies: reality check. J Clin Pharmacol 47:1104–1118PubMedCrossRefGoogle Scholar
  25. 25.
    Bruno R, Washington CB, Lu JF, Lieberman G, Banken L, Klein P (2005) Population pharmacokinetics of trastuzumab in patients with HER2+ metastatic breast cancer. Cancer Chemother Pharmacol 56:361–369PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • R. Paridaens
    • 1
  • O. Rixe
    • 2
  • M. C. Pinel
    • 3
  • H. Wildiers
    • 1
  • G. Zorza
    • 3
  • P. Ferré
    • 3
    Email author
  • H. Roche
    • 4
  1. 1.Department of General Medical Oncology, Leuven Cancer InstituteUniversity Hospitals Borst CentrumLeuvenBelgium
  2. 2.Hôpital Pitié-SalpêtrièreParisFrance
  3. 3.Institut de Recherche Pierre FabreToulouse Cedex 01France
  4. 4.Institut Claudius RegaudToulouseFrance

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